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Ligand activation of peroxisome proliferator-activated receptor γ induces apoptosis of leukemia cells by down-regulating the c-myc gene expression via blockade of the Tcf-4 activity | Cell Death & Differentiation
Description:
The peroxisome proliferator-activated receptor γ (PPAR γ), a member of the nuclear receptor superfamily, is expressed at highest levels in adipose tissue and functions as a central regulator in the process of adipocyte differentiation. In the present study, we showed that human leukemic cell lines, not only myeloid but also lymphoid, express PPAR γ and its activation by natural ligand (15-deoxy-Δ12,14 - prostaglandin J2) and synthetic ligand (troglitazone) profoundly inhibited their proliferation by induction of apoptosis preferentially in the serum-free culture. We pursued its mechanism using the representative cell lines, and found that induction of apoptosis was accompanied by caspase-3 activation and specifically blocked by its inhibitor. While status of several apoptosis-related molecules remained unchanged, the c-Myc expression was markedly down-regulated within 24 h after troglitazone treatment. The c-myc mRNA levels were dramatically reduced at 1 h and became undetectable at 12 h after troglitazone treatment, which proved to be accompanied by complete blockade of the Tcf-4 activity in the electrophoretic mobility shift assay. We succeeded in establishing HL-60 cell lines growing well in the presence of troglitazone in the long-term serum-free culture. They showed neither induction of apoptosis nor down-regulation of the c-Myc expression via blockade of the Tcf-4 activity after troglitazone treatment. This is the first identification of the linkage between PPAR γ-mediated apoptosis and down-regulation of the c-myc gene expression.
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cell, troglitazone, cells, cmyc, ppar, expression, μgml, google, scholar, article, lanes, apoptosis, cas, tcf, activation, treatment, lines, dmemf, figure, activity, shown, receptor, lane, cultured, resistant, presence, leukemia, downregulation, peroxisome, culture, nature, antibody, medium, nuclear, line, concentrations, differentiation, human, inhibition, fcs, nfκb, data, ligand, proliferatoractivated, dna, induces, induction, open, addition, caspase,
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n-benzyloxycarbonyl-asp-glu-val-asp-fluoromethylketone nature portfolio permissions reprints privacy policy macrophage nature 391 peroxisome proliferator-activated receptor-γ receptors nature 358 advertising fcs-free d-mem/f12 medium c-myc proto-oncogene product long-term serum-free culture peroxisome proliferator-activated receptor selective inhibitor z-devd-fmk peroxisome proliferator-activated receptors social media wright–giemsa staining nature 10% fcs-d-mem/f12 medium ccaat/enhancer-binding protein α proliferator-activated receptors α peroxisome-proliferated receptor γ author correspondence human monocyte-derived macrophages middle full-scaled ligand activation apc/β-catenin/tcf-4 pathway map kinase-mediated phosphorylation murine b-lymphoma cells ligand-activated transcription factors repress mir-28-5p/ezh2 d-mem/f12 medium c-myc promoter proc c-myc gene product viral oncogene v-myc c-myc proto-oncogene protein a-sepharose beads α-32p-dctp-labeled 1 human c-myc promoter peroxisomal β-oxidation pathway oncogene-induced replication stress zinc-inducible expression plasmids b-lymphoid cell lines oral anti-diabetic agents transmit anti-apoptotic signal 32p-labeled tcf-4 oligonucleotide murine c-myc promoter anti-ppar γ antibody counteracting anti-apoptotic proteins nf-κb p65 subunit c-myc gene expression
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datePublished:2002-04-25T00:00:00Z
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